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WO2021214126A1 - Conjugués médicament-anticorps - Google Patents

Conjugués médicament-anticorps Download PDF

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Publication number
WO2021214126A1
WO2021214126A1 PCT/EP2021/060352 EP2021060352W WO2021214126A1 WO 2021214126 A1 WO2021214126 A1 WO 2021214126A1 EP 2021060352 W EP2021060352 W EP 2021060352W WO 2021214126 A1 WO2021214126 A1 WO 2021214126A1
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WO
WIPO (PCT)
Prior art keywords
substituted
group
alkylene
antibody
unsubstituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2021/060352
Other languages
English (en)
Inventor
Alfonso Latorre Lozano
Valentín MARTÍNEZ BARRASA
Andrés M. FRANCESCH SOLLOSO
María del Carmen CUEVAS MARCHANTE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmamar SA
Original Assignee
Pharmamar SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to AU2021260792A priority Critical patent/AU2021260792C1/en
Priority to BR112022020823A priority patent/BR112022020823A2/pt
Priority to CA3175426A priority patent/CA3175426A1/fr
Priority to CR20220581A priority patent/CR20220581A/es
Priority to EP21719647.6A priority patent/EP4138923A1/fr
Priority to JP2022564039A priority patent/JP2023522259A/ja
Priority to US17/920,000 priority patent/US20240131180A1/en
Priority to KR1020227040525A priority patent/KR20230004714A/ko
Priority to PE2022002459A priority patent/PE20230785A1/es
Application filed by Pharmamar SA filed Critical Pharmamar SA
Priority to MX2022013298A priority patent/MX2022013298A/es
Priority to CN202180029877.1A priority patent/CN115427081B/zh
Priority to PH1/2022/552706A priority patent/PH12022552706A1/en
Priority to IL297028A priority patent/IL297028A/en
Publication of WO2021214126A1 publication Critical patent/WO2021214126A1/fr
Priority to DO2022000224A priority patent/DOP2022000224A/es
Anticipated expiration legal-status Critical
Priority to CONC2022/0016548A priority patent/CO2022016548A2/es
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A61K47/6855—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell the tumour determinant being from breast cancer cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6889—Conjugates wherein the antibody being the modifying agent and wherein the linker, binder or spacer confers particular properties to the conjugates, e.g. peptidic enzyme-labile linkers or acid-labile linkers, providing for an acid-labile immuno conjugate wherein the drug may be released from its antibody conjugated part in an acidic, e.g. tumoural or environment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D515/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D515/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings

Definitions

  • WO2018197663 is directed to novel ecteinascidin derivatives which demonstrate very promising anti-tumor activity.
  • One of the compounds disclosed in such patent application is currently in Phase I clinical trials for the prevention and treatment of solid tumors.
  • Ab is a moiety comprising at least one antigen binding site; and n is the ratio of the group [D-(X) b -(AA) w -(T) g -(L)-] to the moiety comprising at least one antigen binding site and is in the range from 1 to 20.
  • a drug conjugate comprising a drug moiety covalently attached to the rest of the drug conjugate, the drug conjugate having formula [D-(X) b -(AA) w -(T) g -(L)-] n -Ab wherein:
  • D is a drug moiety having the following formula (I) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein:
  • R 1 is -OH or -CN
  • X and T are extending groups that may be the same or different; each AA is independently an amino acid unit;
  • D is a drug moiety having the following formula (I) or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof,
  • Y is -NH- or -O-
  • R 3 is hydrogen or a -OR b group
  • R a is selected from hydrogen, substituted or unsubstituted C 1 -C 12 alkyl, substituted or unsubstituted C 2 -C 12 alkenyl, and substituted or unsubstituted C 2 -C 12 alkynyl;
  • X and T are extending groups that may be the same or different; each AA is independently an amino acid unit;
  • L 1 is a linker selected from the group of formulas consisting of: each of the the wavy lines indicates the point of covalent attachment to (T) g if any, or (AA) w if any, or to (X) b if any, or to D;
  • G is selected from halo, -O-mesyl and -O-tosyl;
  • the alkynyl group in the definitions of R a , R b , R c and R x are branched or unbranched, and may have one or more triple bonds and from 2 to 12 carbon atoms. Preferably, they have from 2 to 6 carbon atoms, and more preferably they are branched or unbranched alkynyl groups having 2, 3 or 4 carbon atoms.
  • the heterocycloalkyl groups in the definitions of R y and R z comprise an alkyl group as defined and exemplified above which is substituted with one or more heterocyclyl groups as defined and exemplified above.
  • the heterocycloalkyl groups comprise an alkyl group having from 1 to 6 carbon atoms which is substituted with a heterocyclyl group having from 5 to 10 ring atoms in 1 or 2 ring atoms and can be aromatic, partially saturated or fully saturated.
  • the heterocycloalkyl groups comprise a methyl or ethyl group which is substituted with a heterocyclyl group selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, oxanyl, thianyl, 8-quinolyl, isoquinolyl, pyridyl, pyrazinyl, pyrazolyl, pyrimidinyl, furyl, pyrrolyl, thienyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, isoxazolyl, oxazolyl and benzimidazole.
  • a heterocyclyl group selected from the group consisting of pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl
  • the heterocyclo groups in the definition of R 19 are heterocyclyl groups containing from 1 to 3 separated or fused rings having from 5 to 12 ring atoms and comprising at least one oxygen, nitrogen or sulphur atom in said ring(s), wherein there are two covalent bonds at any position on the ring system of said heterocyclic groups.
  • R3 is hydrogen or a -OR b group
  • Prot NH is a protecting group for amino; wherein substituted groups are substituted with one or more substituents R x that are independently selected from the group consisting of C 1 -C 12 alkyl groups which may be optionally substituted with at least one group R y , C 2 -C 12 alkenyl groups which may be optionally substituted with at least one group R y , C 2 -C 12 alkynyl groups which may be optionally substituted with at least one group R y , halogen atoms, oxo groups, thio groups, cyano groups, nitro groups, OR y , OCOR y , OCOOR y , COR y , COOR y , OCONR y R z , CONR y R z , groups having from 6 to 18 carbon atoms in one or more rings which may optionally be substituted with one or more substituents which may be the same or different selected from the group consisting of R y , OR y ,
  • Y is -NH-; and R 1 ; R 2 ; R 3 ; R 4 ; R a ; R t> ; R c ; and Prot NH are as defined as above.
  • R 1 is -OH; and R 2 ; R 3 ; R 4 ; R a ; R b ; R c ; and Prot NH are as defined as above.
  • R 3 is hydrogen or a -OR b group; where R b is a substituted or unsubstituted C 1 -C 6 , alkyl. Particularly preferred R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl and substituted or unsubstituted tert-butyl. More preferred R are hydrogen and methoxy, being methoxy the most preferred R group;
  • R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted «- propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted /7-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl.
  • Most preferred R c is methyl.
  • More preferred R 4 is selected from hydrogen, -CH 2 OH and -CH 2 NH 2 . More preferably, R 4 may be hydrogen, -CH 2 OH. Most preferred R 4 is hydrogen.
  • R 1 is -OH
  • R 3 is hydrogen or a -OR b group; where R b is a substituted or unsubstituted C 1 -C 6 , alkyl. Particularly preferred R b is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted /7-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec -butyl and substituted or unsubstituted tert- butyl.
  • R3 are hydrogen and methoxy, being methoxy the most preferred R3 group; and R2; R4; R a ; R c ; and Prot NH are as defined as above.
  • Further preferred drug moieties and drugs include moieties of general formula (I) or
  • R 1 is -OH
  • R c is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted «- propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl , and substituted or unsubstituted tert-butyl.
  • Most preferred R c is methyl.
  • More preferred R 4 is selected from hydrogen, -CH 2 OH and -CH 2 NH 2 . More preferably, R 4 may be hydrogen or -CH 2 OH.
  • Most preferred R 4 is hydrogen; and R 1 is as defined as above.
  • R 4 is selected from hydrogen, -CH 2 OH, and -CH 2 NH 2 .
  • Y is -O-
  • R a is selected from hydrogen and substituted or unsubstituted C 1 -C 6 , alkyl; and R b is substituted or unsubstituted C 1 -C 6 , alkyl.
  • Y is -NH-
  • R 3 is hydrogen or methoxy
  • R 3 is hydrogen or methoxy
  • R 3 is methoxy; and R 4 is hydrogen.
  • X and T are extending groups as defined herein; each AA is independently an amino acid unit as defined herein; w is an integer ranging from 0 to 12; b is an integer of 0 or 1 ; g is an integer of 0 or 1 ; where b+g+w is optionally not 0;
  • D is a drug moiety
  • R 30 is a -C 2 -C 4 alkylene- group
  • R x selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, halogen atoms, nitro groups and cyano groups;
  • R x selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, halogen atoms, nitro groups and cyano groups)-NH-;
  • Another preferred drug conjugate of formula [D-(X) b -(AA) w -(T) g -(L)-] n -Ab according to the present invention is one wherein L, (AA) w , (X) b , and (T) g are as defined above and wherein D is a compound of formula (I) or (IH), or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof, wherein Y is -NH- or 0
  • a further preferred drug conjugate of formula [D-(X) b -(AA) w -(T) g -(L)-] n -Ab according to the present invention is one wherein L, (AA) w , (X) b , (T) g and D are as defined above and the moiety Ab comprising at least one antigen binding site is an antibody or antigen-binding fragment thereof, wherein the antibody or antigenbinding fragment thereof is an antigen-binding fragment selected from the group consisting of an Fab fragment, an Fab’ fragment, an F(ab’)2 fragment and an Fv fragment.
  • Necitumumab Nimotuzumab, Nivolumab, Obinutuzumab, Ofatumumab,
  • Olaratumab Panitumumab, Pembrolizumab, Pertuzumab, Pinatuzumab,
  • L is selected from the group consisting of: wherein: the wavy lines indicate the point of covalent attachments to an Ab (the wavy line to the right) and to (T) g if any, or (AA) w if any, or to (X) b if any, or to (D) (the wavy line to the left);
  • R 19 is selected from -C 1 -C 12 alkylene-, -O-(C 1 -C 12 alkylene), -C 6 -C 12 arylene in one or more rings which may optionally be substituted with one or more substituents R x , -C 1 -C 12 alkylene - C 6 -C 12 arylene- wherein the arylene group is in one or more rings which may optionally be substituted with one or more substituents R x , -C 6 -C 12 arylene-C 1 -C 12 alkylene- wherein the arylene group is in one or more rings which may optionally be substituted with one or more substituents R x , -C 5 -C 12 heterocyclo- wherein said heterocyclo group may be a saturated or unsaturated group having one or more rings and comprising at least one oxygen, nitrogen or sulphur atom in said ring(s), said group optionally being substituted with one or more substituents R x ,
  • R3 is hydrogen or a -OR b group, wherein R b is a substituted or unsubstituted C 1 -C 6 , alkyl group, wherein the optional substituents are one or more substituents R x ;
  • R4 is selected from hydrogen, -CH 2 OH and -CH 2 NH 2 ;
  • the moiety Ab comprising at least one antigen binding site is an antibody or an antigen- binding fragment thereof and it is selected from the group consisting of a human antibody, an antigen-binding fragment of a human antibody, a humanized antibody, an antigen-binding fragment of a humanized antibody, a chimeric antibody, an antigen-binding fragment of a chimeric antibody, a glycosylated antibody and a glycosylated antigen binding fragment; and n is the ratio of the group [D-(X) b -(AA) w -(T) g -(L)-] to the moiety Ab comprising at least one antigen binding site and is in the range from 1 to 12.
  • M is selected from the group consisting of -C 1 -C 3 alkylene- and -C 1 -C 3 alkylene-(C 5 -C 7 carbocyclo)-;
  • (AA) w is of formula (II) wherein: the wavy lines indicate the point of covalent attachments to (X) b if any, or to the drug moiety (the wavy line to the left) and to (T) g if any, or to the linker (the wavy line to the right);
  • X is an extending group selected from the group consisting of where D is conjugated via an amine group: -COO-(C 2 -C 4 alkylene)NH-, -COO-CH 2 - phenylene-NH-, wherein said phenylene group may optionally be substituted with from one to four substituents R x selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, halogen atoms, nitro groups and cyano groups, -COO-(C 2 -C 4 alkylene)NH-COO-CH 2 -(phenylene which may optionally be substituted with from one to four substituents R x selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, halogen atoms, nitro groups and cyano groups)-NH-, -COCH 2 NH-COCH 2 -NH-
  • R 2 is acetyl
  • R 30 is a -C 2 -C 4 alkylene- group
  • M is -C 1 -C 3 alkylene-(C 5 -C 7 carbocyclo)-; w is 0 or 2, and where w is 2, then (AA) w is of formula (III): wherein the wavy lines indicate the point of covalent attachments to (X) b if any, or to the drug moiety (the wavy line to the left) and to (T) g if any, or to the linker (the wavy line to the right);
  • R 22 is selected from methyl, benzyl, isopropyl, ,sw-butyl and indolylmethyl;
  • X is an extending group selected from the group consisting of -COO-(C 2 C 4 alkylene)NH-, - COO-CH 2 -phenylene-NH-, wherein said phenylene group may optionally be substituted with from one to four substituents R x selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, halogen atoms, nitro groups and cyano groups, -COO-(C 2 C 4 alkylene)NH-COO-CH 2 -(phenylene which may optionally be substituted with from one to four substituents R x selected from the group consisting of alkyl groups having from 1 to 6 carbon atoms, alkoxy groups having from 1 to 6 carbon atoms, halogen atoms, nitro groups or cyano groups)-NH-, -COCH 2 NH-COCH 2 -NH-,- COO-(C 2 -C 4 alkylene)
  • R2 is acetyl
  • Y is -NH- or -O-;
  • the moiety Ab comprising at least one antigen binding site is a monoclonal antibody selected from the group consisting of Alemtuzumab, Anetumab, Atezolizumab, Avelumab, Bevacizumab, Blinatomumab, Brentuximab, Catumaxomab, Cetuximab, Coltuximab, Daratumumab, Denintuzumab, Denosumab, Depatuxizumab, Dinutuximab, Durvalumab, Elotuzumab, Enfortumab, Glembatumumab, Gemtuzumab, Ibritumomab, Indatuximab, Indusatumab, Inotuzumab, Ipilimumab, Labetuzumab, Ladiratuzumab, Laprituximab, Lifastuzumab, Lor
  • n is the ratio of the group [D-(X) b -(AA) w -(T) g -(L)-] wherein L is as defined in formulas (IV), (V) or (VI) to the moiety Ab comprising at least one antigen binding site and is in the range from 3 to 5.
  • R 19 is -C 2 -C 6 alkylene-
  • M is -C 1 -C 3 alkylene-(C 5 -C 7 carbocyclo)-; w is 0 or 2, and where w is 2, then (AA) w is of formula (III): wherein R 22 is isopropyl, R 23 is selected from methyl and -(CH 2 ) 3 NHCONH 2 , wherein the wavy lines indicate the point of covalent attachments to (X) b if any, or to the drug moiety (the wavy line to the left) and to (T) g if any, or to the linker (the wavy line to the right);
  • X is a -COOCH 2 -phenylene-NH group; b is 1;
  • T is an extending group of formula -CO-(C 1 -C 4 alkylene)-[O-(C 2 -C 4 alkylene)]4-NH-; g is O or 1;
  • D is a drug moiety selected from: or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof; wherein the wavy line indicates the point of covalent attachment to (X) b ; the moiety Ab comprising at least one antigen binding site is Brentuximab, Gemtuzumab, Inozutumab, Rovalpituzumab, an anti-HER2 antibody such as Trastuzumab, an anti-CD4 antibody, an anti-CD5 antibody, an anti-CD 13 antibody and an anti-CD30 antibody, or an antigen-binding fragment or an immunologicallly active portion thereof, and more preferably its is selected from an anti-HER2 antibody such as Trastuzumab and anti-CD 13 antibody or an antigen-binding fragment or an immunologically active portion thereof, particularly Trastuzumab or an antigen-binding fragment or an immunologicallly active portion thereof; and n is the ratio of the group [D-(X) b -(AA
  • n is from 2 to 6, more preferably 3, 4, or 5 and each is independently selected from Brentuximab, Gemtuzumab, Inozutumab, Rovalpituzumab, an anti-HER2 antibody such as Trastuzumab, an anti-CD4 antibody, an anti-CD5 antibody, an anti-CD 13 antibody and an anti-CD30 antibody, or an antigen-binding fragment or an immunologically active portion thereof, and more preferably its is selected from an anti- HER2 antibody such as Trastuzumab and anti-CD 13 antibody or an antigen-binding fragment or an immunologically active portion thereof, particularly Trastuzumab or an antigen-binding fragment or an immunologically active portion thereof.
  • an anti-HER2 antibody such as Trastuzumab and anti-CD 13 antibody or an antigen-binding fragment or an immunologically active portion thereof, particularly Trastuzumab or an antigen-binding fragment or an immunologically active portion thereof.
  • HER2 antibody such as Trastuzumab and an anti-CD 13 antibody or an antigen-binding fragment or an immunologically active portion thereof, more preferably is Trastuzumab or an antigen-binding fragment or an immunologically active portion thereof,
  • Preferred compounds of formula D-(X) b -(AA) w -(T) g -L 1 or of formula D-(X) b -(AA) w -(T) g -H according to the present invention include: ⁇ a compound of formula D-(X) b -(AA) w -(T) g -L 1 or of formula D-(X) b -(AA) w -(T) g -H wherein each of D, X, AA, T, L 1 , b, g and w are as defined herein in the present invention; but further wherein if the compound is a compound of formula D-(X) b - (AA) w -(T) g -H then b+w+g10.
  • L 1 is a linker of formula: wherein: the wavy line indicates the point of covalent attachment to (T) g if any, or (AA) w if any, or to (X) b if any, or to D;
  • L 1 is linker of formula: wherein: the wavy line indicates the point of covalent attachment to (T) g if any, or (AA) w if any, or to (X) b if any, or to D;
  • R 19 is selected from -C 1 -C 8 alkylene-, -O-(C 1 -C 8 alkylene), -C 1 -C 8 alkylene-Ce-Cn arylene- wherein the arylene group is in one or more rings which may optionally be substituted with one or more substituents R x , and -C 6 -C 12 arylene-C 1 -C 8 alkylene- wherein the arylene group is in one or more rings which may optionally be substituted with one
  • T is an extending group selected from -CO-(C 1 -C 4 alkylene)-NH-; -CO-(C 1 -C 4 alkylene)- [O- (C 2 -C 4 alkylene)] j -NH- and -COO-(C 1 -C 4 alkylene)-[0-(C 2 -C 4 alkylene)] j -NH-, where j is an integer from 1 to 10; b is 0 or 1 ; g is O or 1; wherein if the compound is a compound of formula D-(X) b -(AA) w -(T) g -H then b+w+g10; and D is a drug moiety of formula (I); and is covalently attached via a hydroxy or amine group; or is a drug moiety of formula (IH), or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof wherein: wherein the wavy line of (
  • R 1 is -OH or -CN
  • R3 is hydrogen or a -OR b group wherein R b is a substituted or unsubstituted C 1 -C 6 , alkyl group, wherein the optional substituents are one or more substituents R x ;
  • R4 is selected from hydrogen, -CH2OH and -CH2NH2;
  • Y is -NH- or -O-.
  • R 22 is selected from methyl, benzyl, isopropyl, ,sw-butyl and indolylmethyl;
  • T is an extending group selected from -CO-(C 1 -C 4 alkylene)-NH-, -CO-(C 1 -C 4 alkylene)- [0-(C 2 -C 4 alkylene)] j -NH-, and -COO-(C 1 -C 4 alkylene)- [0-(C 2 -C 4 alkylene)] j -NH-, where j is an integer from 1 to 5; b is 0 or 1 ; g is O or 1; wherein if the compound is a compound of formula D-(X) b -(AA) w -(T) g -H then b+w+g10; and
  • R 19 is -C 2 -C 6 alkylene-; w is 0 or 2, and where w is 2, then (AA) w is of formula (III): R 22 is isopropyl, R 23 is selected from methyl and -(CH 2 ) 3 NHCONH 2 , wherein the wavy lines indicate the point of covalent attachments to X (the wavy line to the left) and to (T) g if any, or L 1 or to a hydrogen atom (the wavy line to the right);
  • X is an extending group selected from -COO-CH 2 -phenylene-NH-, -COO(CH2)3NHCOO- CH 2 -phenylene-NH, -COO-(CH 2 ) 3 )NH-, -COO(CH 2 ) 3 -S-, and -COO-(CH 2 ) 3 NHCO-(CH 2 ) 2 S-;
  • T is a -CO-(CH 2 ) 2 -[0-(CH 2 ) 2 ] 4 -NH- group; b is 0 or 1 ; g is O or 1; wherein if the compound is a compound of formula D-(X) b -(AA) w -(T) g -H then b+w+g10; and D is a drug moiety selected from: or a pharmaceutically acceptable salt, ester, solvate, tautomer or stereoisomer thereof; wherein the wavy line indicates the point of covalent attachment.
  • a compound of formula D-X-(AA) w -(T) g -L 1 selected from:
  • alkali addition salts include inorganic salts such as, for example, sodium, potassium, calcium and ammonium salts, and organic alkali salts such as, for example, ethylenediamine, ethanolamine, /V,/V-di alkyl diethanolamine, triethanolamine and basic aminoacids salts.
  • esters are not particularly restricted, and can be selected by a person with an ordinary skill in the art.
  • esters it is preferable that such esters can be cleaved by a biological process such as hydrolysis in vivo.
  • the group constituting the said esters can be, for example, a C 1 -C 4 alkoxy C 1 -C 4 alkyl group such as methoxyethyl, 1 -ethoxy ethyl, 1-methyl-l- methoxyethyl, l-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxy ethyl, 1,1 -dimethyl- 1- methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t- butoxymethyl; a C 1 -C 4 alkoxylated C 1 -C 4 alkoxy C 1 -C 4 alkyl group such as 2- methoxyethoxymethyl; a C 6- C 10 aryloxy C 1 -C 4 alkyl group such as phenoxymethyl; a halogenated C 1 -C 4 alkoxy C 1 -C 4 alkyl group such as methoxyethyl, 1 -eth
  • the protecting group for the OH can be selected from methyl, methoxymethyl, methylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p- methoxybenzyloxymethyl, [(3, 4-dimethoxybenzyl)oxy] methyl, p-nitrobcnzyloxy methyl, o- nitrobenzyloxymethyl, [(7?)- 1 -(2-nitrophenyl)ethoxy]methyl, (4-methoxyphenoxy)methyl, guaiacolmethyl, [(p-phenylphenyl)oxy] methyl, Z-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2-cyanoethoxymethyl, bis(2-chloroethoxy)methyl, 2,2,2-trichloroethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, menthoxymethyl, 0-bis(2- acetoxy-ethoxy)
  • the antibody in the drug conjugates of the present invention may bind to a receptor encoded by the ErbB gene.
  • the antibody may bind specifically to an ErbB receptor selected from EGFR, HER2, HER3 and HER4.
  • the antibody in the drug conjugate may specifically bind to the extracellular domain of the HER2 receptor and inhibit the growth of tumour cells which overexpress the HER2 receptor.
  • the antibody of the drug conjugate may be a monoclonal antibody, e.g. a murine monoclonal antibody, a chimeric antibody, or a humanised antibody.
  • the drug antibody conjugates of the present invention can be prepared according to techniques that are well known in the art. Processes for conjugating moieties comprising at least one antigen binding site antibodies such as antibodies to a number of different drugs using different processes have been described and exemplified previously in, for example, WO-A-2004/010957, WO-A-2006/060533 and WO-A-2007/024536, the contents of which are incorporated herein by reference thereto. These involve use of a linker group that derivatises the drug, toxin or radionuclide in such a way that it can then be attached to the moiety such as an antibody.
  • the antibody is selected from Brentuximab, Gemtuzumab, Inozutumab, Rovalpituzumab, an anti-HER2 antibody such as Trastuzumab, an anti-CD4 antibody, an anti-CD5 antibody, an anti-CD 13 antibody and an anti-CD30 antibody, or an antigen-binding fragment or an immunologically active portion thereof, or it is selected from an anti-HER2 antibody such as Trastuzumab and anti-CD 13 antibody or an antigen- binding fragment or an immunologically active portion thereof, and most preferably it is Trastuzumab or an antigen-binding fragment or an immunologically active portion thereof.
  • Another example of a process for the preparation of a drug antibody conjugate of the present invention involves the preparation of drug antibody conjugates of formula (O) or (P) as follows: said process comprising the following steps: (i) either:
  • the partially reduced monoclonal antibody is an anti-HER2 antibody such as Trastuzumab or an anti-CD 13 antibody or an antigen-binding fragment or an immunologically active portion thereof, preferably Trastuzumab or an antigen-binding fragment or an immunologically active portion thereof; or preferably an anti-CD 13 antibody or an antigen-binding fragment or an immunologically active portion thereof.
  • an anti-HER2 antibody such as Trastuzumab or an anti-CD 13 antibody or an antigen-binding fragment or an immunologically active portion thereof, preferably Trastuzumab or an antigen-binding fragment or an immunologically active portion thereof; or preferably an anti-CD 13 antibody or an antigen-binding fragment or an immunologically active portion thereof.
  • a pharmaceutical composition comprising a drug conjugate according to the present invention and a pharmaceutically acceptable carrier.
  • a drug conjugate having the general formula [D-(X) b -(AA) w -(T) g -(L)- ] n -Ab of the present invention include without limitation oral, topical, parenteral, sublingual, rectal, vaginal, ocular, and intranasal.
  • Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • the compositions are administered parenterally.
  • the pharmaceutically acceptable carrier or vehicle can be particulate, so that the compositions are, for example, in tablet or powder form.
  • the carrier(s) can be liquid, with the compositions being, for example, an oral syrup or injectable liquid.
  • the carrier(s) can be gaseous, so as to provide an aerosol composition useful in, for example, inhalatory administration.
  • carrier refers to a diluent, adjuvant or excipient, with which a drug antibody conjugate of the present invention is administered.
  • Such pharmaceutical carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • composition When intended for oral administration, the composition is preferably in solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
  • the composition can be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form.
  • a solid composition typically contains one or more inert diluents.
  • binders such as carboxymethylcellulose, ethyl cellulose, microcrystalline cellulose, or gelatin; excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, corn starch and the like; lubricants such as magnesium stearate; glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; a flavoring agent such as peppermint, methyl salicylate or orange flavoring; and a coloring agent.
  • the composition can be in the form of a liquid, e.g. an elixir, syrup, solution, emulsion or suspension.
  • the liquid can be useful for oral administration or for delivery by injection.
  • a composition can comprise one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
  • a surfactant, preservative, wetting agent, dispersing agent, suspending agent, buffer, stabilizer and isotonic agent can also be included.
  • the liquid compositions of the invention can also include one or more of the following: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides, polyethylene glycols, glycerin, or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer's solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides, polyethylene glycols, glycerin, or other solvents
  • antibacterial agents such as benzyl alcohol or methyl paraben
  • agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • a parenteral composition can be enclosed in an ampoul
  • compositions comprise an effective amount of a drug conjugate of the present invention such that a suitable dosage will be obtained.
  • the correct dosage of the compounds will vary according to the particular formulation, the mode of application, and its particular site, host and the diease being treated, e.g. cancer and, if so, what type of tumor. Other factors like age, body weight, sex, diet, time of administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose.
  • Pulmonary administration can also be employed, e.g. by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
  • the drug antibody conjugate of the present invention or compositions can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained- release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E. W. Martin.
  • the pharmaceutical compositions can be prepared using methodology well known in the pharmaceutical art. For example, a composition intended to be administered by injection can be prepared by combining a drug conjugate of the present invention with water so as to form a solution. A surfactant can be added to facilitate the formation of a homogeneous solution or suspension.
  • the Moiety comprising at least one antigen binding site of a drug conjugate of the present invention binds to or associates with a cancer-cell or a tumor-cell-associated antigen, and the drug conjugate of the present invention can be taken up inside a tumor cell or cancer cell through receptor-mediated endocytosis.
  • the antigen can be attached to a tumor cell or cancer cell or can be an extracellular matrix protein associated with the tumor cell or cancer cell.
  • one or more specific sequences within the Linker unit are hydrolytically cleaved by one or more tumor-cell or cancer-cell-associated proteases or hydrolases, resulting in release of a Drug or a Drug-Linker Compound.
  • the drug conjugate or composition of the present invention may be administered with radiotherapy. Radiotherapy may be administered at the same time, prior to or after treatment with the drug conjugate or composition of the present invention.
  • the drug conjugate or composition of the present invention is administered concurrently with radiation therapy.
  • the radiation therapy is administered prior or subsequent to administration of a drug conjugate or composition of the present invention, preferably at least an hour, five hours, 12 hours, a day, a week, a month, more preferably several months (e.g. up to three months), prior or subsequent to administration of a drug antibody conjugate or composition of the present invention.
  • any radiation therapy protocol can be used depending upon the type of cancer to be treated.
  • x-ray radiation can be administered; in particular, high-energy megavoltage (radiation of greater that 1 MeV energy) can be used for deep tumors, and electron beam and orthovoltage x-ray radiation can be used for skin cancers.
  • Gamma-ray emitting radioisotopes such as radioactive isotopes of radium, cobalt and other elements, can also be administered.
  • Cl-TrtCl-resin (20 g, 1.49 mmol/g) (Iris Biotech, Ref.: BR-1065, 2-Chlorotrityl chloride resin (200-400 mesh, 1% DVB, 1.0-1.6 mmol/g), CAS 42074-68-0) was placed in a filter plate. 100 ml, of DCM was added to the resin and the mixture was stirred for 1 h. The solvent was eliminated by filtration under vacuum. A solution of Fmoc-Cit-OH (11.83 g, 29.78 mmol) and DIPEA (17.15 mL, 98.45 mmol) in DCM (80 mL) was added and the mixture was stirred for 10 min.
  • the Fmoc-Val-Cit-O-TrtCl -resin thus produced was treated with piperidine: DMF (1:4, l x l min, 2 x 10 min) and washed with DMF (5 x 50 mL x 0.5 min). The final piperidine wash gave NFL-Val-Cit-O-TrtCl-resin.
  • the reaction was stopped by addition of MeOH (10 mL) and stirred 15 min at 23 °C.
  • the Lmoc-Cit-O-TrtCl-resin was subjected to the following washing/treatments: CH2CI2 (5 x 15 mL x 0.5 min), DML (5 x 15 mL x 0.5 min), piperidine :DML (1:4, 15 mL, l x l min, 2 x 10 min), DML (5 x 15 mL x 0.5 min), CH2CI2 (5 x 15 mL x 0.5 min).
  • the loading was calculated: 1.17 mmol/g.
  • the peptide was cleaved from the resin by treatments with TFA:CH 2 CI (1:99, 5 x 50 mL). The resin was washed with CH2CI2 (7 x 50 mL x 0.5 min). The combined filtrates were evaporated to dryness under reduced pressure, the solid obtained was triturated with Et20 and filtrated to obtain LIN 2-1 (4.59 g, 87% yield) as a white solid.
  • Cl-TrtCl-resin (5 g, 1.49 mmol/g) was placed in a filter plate. To the resin was added CH2CI2 (25 mL) and the mixture was stirred for 1 h at 23 °C. The solvent was eliminated by filtration over vacuum. A solution of Fmoc-Ala-OH (2.31 g, 7.41 mmol) and DIPEA (4.28 mL, 24.61 mmol) in CH2CI2 (20 mL) was added and the mixture was stirred for 10 min at 23 °C. DIPEA (8.60 mL, 49.37 mmol) was additionally added and the reaction mixture was stirred for 1 h at 23 °C.
  • the reaction was stopped by addition of MeOH (10 mL) and stirred 15 min at 23 °C.
  • the Lmoc-Ala-O-TrtCl-resin was subjected to the following washing/treatments: CH2CI2 (5 x 15 mL x 0.5 min), DML (5 x 15 mL x 0.5 min), piperidine :DML (1:4, 15 mL, l x l min, 2 x 10 min), DML (5 x 15 mL x 0.5 min), CH2CI2 (5 x 15 mL x 0.5 min).
  • the loading was calculated: 1.34 mmol/g.
  • the NPh-Ala-O-TrtCl-resin was washed with DML (5 x 15 mL x 0.5 min) and a solution of Lmoc-Val-OH (9.09 g, 26.79 mmol) and HOBt (3.62 g, 26.79 mmol) in DML (25 mL) was added to the NPL-Ala-O-TrtCl-resin followed by addition DIPCDI (4.14 mL, 26.79 mmol) at 23 °C. The mixture was stirred for 1.5 h at 23 °C. The reaction was stopped by washing with DML (5 x 15 mL x 0.5 min).
  • the Lmoc-Val-Ala-O-TrtCl-resin was treated with piperidine: DML (1:4, 15 mL, l x l min, 2 x 10 min) and washed with DML (5 x 15 mL x 0.5 min).
  • the peptide was cleaved from the resin by treatments with TLA:CH2Cl2 (1:99, 5 x 50 mL). The resin was washed with CH2CI2 (7 x 50 mL x 0.5 min). The combined filtrates were evaporated to dryness under reduced pressure, the solid obtained was triturated with Et20 and filtrated to obtain L 3-1 (4.73 g, 87% yield) as a white solid.

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Abstract

La présente invention concerne des conjugués de médicament ayant la formule [D-(X)b-(AA)w-(T)g-(L)-]n-Ac dans laquelle : D représente une fraction de médicament ayant la formule suivante (I) ou un sel, un ester, un solvate, un tautomère ou un stéréo-isomère de celle-ci de qualité pharmaceutique, (I) dans laquelle D est lié de manière covalente par l'intermédiaire d'un groupe hydroxyle ou amine à (X)b le cas échéant, ou à (AA)w le cas échéant, ou à (T)g le cas échéant, ou à (L) ; qui sont utiles dans le traitement du cancer.
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WO2024186263A1 (fr) 2023-03-07 2024-09-12 Axcynsis Therapeutics Pte. Ltd. Conjugués anticorps-médicament comprenant de la trabectédine et des dérivés de lurbinectédine

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TWI824043B (zh) * 2018-10-25 2023-12-01 西班牙商瑪製藥股份有限公司 藥物抗體共軛物
WO2025055920A1 (fr) * 2023-09-11 2025-03-20 泰诚思(上海)生物医药有限公司 Nouveau dérivé d'ectéinascidine, son procédé de préparation et son utilisation, conjugué anticorps-médicament et son utilisation

Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US5149804A (en) 1990-11-30 1992-09-22 The Board Of Trustees Of The University Of Illinois Ecteinascidins 736 and 722
WO1994004690A1 (fr) 1992-08-17 1994-03-03 Genentech, Inc. Immunoadhesines bispecifiques
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5569825A (en) 1990-08-29 1996-10-29 Genpharm International Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
WO1997034631A1 (fr) 1996-03-18 1997-09-25 Board Of Regents, The University Of Texas System Domaines analogues a l'immunoglobuline a demi-vies prolongees
WO2003014127A1 (fr) 2001-08-07 2003-02-20 Pharma Mar, S.A. Analogues antitumoraux
WO2003066638A2 (fr) 2002-02-04 2003-08-14 Pharma Mar, S.A.U. Synthese d'ecteinascidines naturelles et composes associes
WO2004010957A2 (fr) 2002-07-31 2004-02-05 Seattle Genetics, Inc. Conjugues de medicaments et leur utilisation dans le traitement du cancer, d'une maladie auto-immune ou d'une maladie infectieuse
WO2006060533A2 (fr) 2004-12-01 2006-06-08 Genentech, Inc. Conjugues medicament anticorps et procedes correspondants
WO2007024536A2 (fr) 2005-08-24 2007-03-01 Immunogen, Inc. Procede de preparation de conjugues medicamenteux purifies
WO2018197663A1 (fr) 2017-04-27 2018-11-01 Pharma Mar, S.A. Composés anticancéreux

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB201309807D0 (en) * 2013-05-31 2013-07-17 Pharma Mar Sau Antibody drug conjugates

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US5633425A (en) 1990-08-29 1997-05-27 Genpharm International, Inc. Transgenic non-human animals capable of producing heterologous antibodies
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5569825A (en) 1990-08-29 1996-10-29 Genpharm International Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5625126A (en) 1990-08-29 1997-04-29 Genpharm International, Inc. Transgenic non-human animals for producing heterologous antibodies
US5661016A (en) 1990-08-29 1997-08-26 Genpharm International Inc. Transgenic non-human animals capable of producing heterologous antibodies of various isotypes
US5149804A (en) 1990-11-30 1992-09-22 The Board Of Trustees Of The University Of Illinois Ecteinascidins 736 and 722
WO1994004690A1 (fr) 1992-08-17 1994-03-03 Genentech, Inc. Immunoadhesines bispecifiques
WO1997034631A1 (fr) 1996-03-18 1997-09-25 Board Of Regents, The University Of Texas System Domaines analogues a l'immunoglobuline a demi-vies prolongees
WO2003014127A1 (fr) 2001-08-07 2003-02-20 Pharma Mar, S.A. Analogues antitumoraux
WO2003066638A2 (fr) 2002-02-04 2003-08-14 Pharma Mar, S.A.U. Synthese d'ecteinascidines naturelles et composes associes
WO2004010957A2 (fr) 2002-07-31 2004-02-05 Seattle Genetics, Inc. Conjugues de medicaments et leur utilisation dans le traitement du cancer, d'une maladie auto-immune ou d'une maladie infectieuse
WO2006060533A2 (fr) 2004-12-01 2006-06-08 Genentech, Inc. Conjugues medicament anticorps et procedes correspondants
WO2007024536A2 (fr) 2005-08-24 2007-03-01 Immunogen, Inc. Procede de preparation de conjugues medicamenteux purifies
WO2018197663A1 (fr) 2017-04-27 2018-11-01 Pharma Mar, S.A. Composés anticancéreux

Non-Patent Citations (37)

* Cited by examiner, † Cited by third party
Title
BOWEN, M. A. ET AL., J. IMMUNOL., vol. 151, 1993, pages 5896 - 5906
BOYD MRPAULL KD, DRUG DEV. RES., vol. 34, 1995, pages 91 - 104
BREITLING, F.DUBEL, S.: "Recombinant Antibodies", 1998, JOHN WILEY, AND SONS
BURGER: "Medicinal Chemistry and Drug Discovery", 2001, WILEY
CARTER ET AL., BIO/TECHNOLOGY, vol. 10, 1992, pages 163 - 167
CARTER ET AL., J. OF HEMATOTHERAPY, vol. 4, 1995, pages 463 - 470
CAS, no. 42074-68-0
CHARI ET AL., CANCER RESEARCH, vol. 52, 1992, pages 127 - 131
CHARI, R.V.: "Targeted cancer therapy: conferring specificity to cytotoxic drugs", ACC. CHEM. RES., vol. 41, 2008, pages 98 - 107, XP008146241, DOI: 10.1021/ar700108g
CLACKSON ET AL., NATURE, vol. 352, 1991, pages 624 - 628
COLE ET AL.: "Monoclonal Antibodies and Cancer Therapy", 1985, HARWOOD ACADEMIC PUBLISHERS, pages: 77 - 96
FAIRCLOTH ET AL., METHODS IN CELL SCIENCE, vol. 11, no. 4, 1988, pages 201 - 205
FRANCISCO, J. A. ET AL., CANCER RES, vol. 60, 2000, pages 3225 - 3231
FRANKE, A. E. ET AL., CANCER BIOTHER RADIOPHARM, vol. 15, 2000, pages 459 - 476
HOLLIGERHUDSON, NATURE BIOTECHNOLOGY, vol. 23, no. 9, 2005, pages 1126 - 1136
KABAT E ET AL., J. OF IMMUNOLOGY, vol. 125, no. 3, 1980, pages 961 - 969
KABAT ET AL.: "Sequences of Proteins of Immunological Interest", 1991, NATIONAL INSTITUTE OF HEALTH
KOHLER ET AL., NATURE, vol. 256, 1975, pages 495
KOZBOR ET AL., IMMUNOLOGY TODAY, vol. 4, 1983, pages 72
LIU ET AL., PROC. NATL. ACAD. SCI. USA, vol. 93, 1996, pages 8618 - 8623
LIU ET AL., PROC. NATL. ACAD. SET (USA, vol. 93, 1996, pages 8618 - 8623
LONBERGHUSZAR, INT. REV. IMMUNOL., vol. 13, 1995, pages 65 - 93
MARKS ET AL., J. MOL. BIOL., vol. 222, 1991, pages 581 - 597
MERCHANT ET AL., NATURE BIOTECHNOLOGY, vol. 16, 1998, pages 677 - 681
MEYER, D.L.SENTER, P.D.: "Recent advances in antibody drug conjugates for cancer therapy", ANNU. REP. MED. CHEM., vol. 38, 2003, pages 229 - 237
MOSMANN ET AL., JOURNAL OF IMMUNOLOGICAL METHODS, vol. 65, no. 1-2, 1983, pages 55 - 63
MURRAY, J. L., SEMIN ONCOL, vol. 27, 2000, pages 64 - 70
NATURE PROTOCOLS, vol. 1, 2006, pages 1112 - 1116
PUREGMAA KHONGORZUL ET AL: "Antibody-Drug Conjugates: A Comprehensive Review", MOLECULAR CANCER RESEARCH, vol. 18, no. 1, 2 January 2020 (2020-01-02), US, pages 3 - 19, XP055723911, ISSN: 1541-7786, DOI: 10.1158/1541-7786.MCR-19-0582 *
RODRIGUES ET AL., J. OF IMMUNOLOGY, vol. 151, 1993, pages 6954 - 6961
SCHECTER ET AL., NATURE, vol. 312, 1984, pages 545 - 548
SKEHAN ET AL., J. NATL. CANCER INST., vol. 82, 1990, pages 1107 - 1112
SURESH ET AL., METHODS IN ENZYMOLOGY, vol. 121, 1986, pages 210
TEICHER BA: "Antibody-drug conjugate targets", CURR CANCER DRUG TARGETS, vol. 9, no. 8, 2009, pages 982 - 1004
TRAIL, P. A. ET AL., SCIENCE, vol. 261, 1993, pages 212 - 215
TRAIL, PA ET AL., CANCER RESEARCH, vol. 57, 1997, pages 100 - 105
WAHL ET AL., CANCER RES., vol. 62, no. 13, 2002, pages 3736 - 3742

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024186263A1 (fr) 2023-03-07 2024-09-12 Axcynsis Therapeutics Pte. Ltd. Conjugués anticorps-médicament comprenant de la trabectédine et des dérivés de lurbinectédine
WO2024186264A1 (fr) 2023-03-07 2024-09-12 Axcynsis Therapeutics Pte. Ltd. Conjugués anticorps-médicament comprenant de la trabectédine et des dérivés de lurbinectédine

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